Having “disease mutational variants” (genotype) but not exhibiting the disease (phenotype)

This is a very interesting exciting study, a great example of “thinking outside the box”. Genetic studies of human Mendelian diseases (one or few mutations in one or few genes) have traditionally focused on detection of the disease-causing mutations in afflicted patients. Generally, it has been strongly agreed upon that these variants cause 100% penetrance, i.e. if you have the mutation, you will develop the disease (time of onset can be variable, due to modifying genes and other factors).

In the study be;pw, authors describe a complementary approach that seeks to identify healthy individuals resilient to highly penetrant forms of genetic childhood disorders. A comprehensive screen of 874 genes in 589,306 genomes––surprisingly(!!!)––resulted in identification of 13 adults harboring mutations for eight severe Mendelian conditions, with no reported clinical manifestation of the indicated disease. To at least some of us geneticists and pediatricians, … this discovery is absolutely mind-boggling.

These findings demonstrate the promise of broadening genetic studies to systematically search for “healthy” individuals who are buffering the effects of rare, highly-penetrant, deleterious mutations. These data also indicate that incomplete penetrance for Mendelian diseases is likely more common than previously believed. The identification of resilient individuals may provide a first step toward uncovering protective genetic variants that could help elucidate the mechanisms of Mendelian diseases and new therapeutic strategies.

Nat Biotechnol2o16; doi:10.1038/nbt.3514(article, not yet in published form) and Naturedoi:10.1038/nature.2016.19719 (editorial about article)